Favorable outcome of COVID-19 in a young woman with severe Crohn’s disease on regular use of adalimumab and prednisone: a case report

Hareton Teixeira Vechi Lucas Rodrigues Maia Manoela do Monte Alves João Firmino Rodrigues-Neto About the authors

ABSTRACT

COVID-19 is a viral disease caused by SARS-CoV-2 that compromises the host immune response in severe cases, promoting a hyperinflammation that results in acute lung injury and multiple organs failure. In this context, patients presenting with immune-related diseases, such as Crohn’s disease, affected by COVID-19, may have an uncertain prognosis. We report on a case of a young female patient with a severe Crohn’s disease that presented with COVID-19 pneumonia and a favorable outcome even maintaining the use of adalimumab, TNF - alpha inhibitor and prednisone. This case raises the hypothesis that aside from prednisone, TNF-α inhibitors such as adalimumab could be used to stop the progression to COVID-19 complications by blocking the TNF-alpha-driven inflammatory process that occurs in severe COVID-19.

COVID-19; Crohn’s disease; TNF inhibitor; SARS-CoV-2

INTRODUCTION

COVID-19 emerged as an important viral disease that spread quickly around the world, and the host immune response seems to be directly related to severe cases of the disease11. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395:1033-4.,22. Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol. 2020;20:355-62.. In these cases, a hyperinflammation is observed resulting in an acute pulmonary injury, designated as the acute respiratory distress syndrome (ARDS), along with multiple organs failure, culminating, in many cases in death11. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395:1033-4.. Higher levels of inflammatory markers, such as C-reactive protein, ferritin, and D- dimer, increased production of inflammatory chemokines and cytokines such as tumor necrosis factor - alpha (TNF-α), interleukin - 6 (IL-6) and IL-7 are observed in severe COVID-19 patients22. Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol. 2020;20:355-62.. Thus, patients with immune-related diseases may represent an important challenge, since the compromise of some immunity pathway can lead to an uncertain prognosis.

In this way, Crohn’s disease (CD) is a chronic condition characterized by intestinal inflammation, being classified among the immune-mediated inflammatory diseases (IMIDs)33. Crespi M, Dulbecco P, De Ceglie A, Conio M. Strictures in Crohn’s disease: from pathophysiology to treatment. Dig Dis Sci. 2020;65:1904-16.,44. Schett G, Sticherling M, Neurath MF. COVID-19: risk for cytokine targeting in chronic inflammatory diseases? Nat Rev Immunol. 2020;20:271-2.. Frequently, the treatment of IMIDs involves targeted interventions that neutralize disease-specific proinflammatory cytokines, such as the use of adalimumab, a TNF-α inhibitor44. Schett G, Sticherling M, Neurath MF. COVID-19: risk for cytokine targeting in chronic inflammatory diseases? Nat Rev Immunol. 2020;20:271-2..

We report here a case of a young female patient with severe Crohn disease affected by COVID-19 pneumonia, who had a favorable outcome even maintaining the use of the TNF-α inhibitor (adalimumab) and prednisone.

CASE REPORT

A 36-year-old caucasian woman sought our emergency department on April 2, 2020 due to a dry cough for 16 days associated with a retrosternal pain. The patient denied dyspnea or hemoptoic sputum. She denied systemic or gastrointestinal symptoms. Her medical history is marked by a severe Crohn disease (CD) diagnosed 9 years before and treated with azathioprine 100 mg/day, adalimumab 40 mg every other week and prednisone 20 mg/day. The last two doses of adalimumab were administered on March 9 and 23, 2020. She had a close contact with a confirmed case of COVID-19 during a work trip on March 10, 2020. She underwent a RT-PCR for SARS-CoV-2 performed with oro- and nasopharyngeal swabs and the RT-PCR result was positive on April 2, 2020.

On admission, vital signs were an axillary temperature of 36.5 ºC, pulse rate 92 beats/min, respiratory rate 18 breathes/min and blood pressure 123/74 mmHg. The physical examination was unremarkable. The peripheral oxygen saturation was 99%. The electrocardiography was normal; chest CT scan showed small, peripheral and bilateral air space consolidations distributed sparsely in the apical segments of the lower lobes and ground-glass opacities in the left upper lobe (Figure 1A). Pleural and pericardial effusions were absent. The laboratory tests showed a mild anemia and thrombocytopenia, but a normal white cells count, accompanied by increased levels of C reactive protein (CRP) and erythrocyte sedimentation rate. The laboratory tests are detailed in Table 1.

Figure 1
The patient’s chest CT showing multiple, bilateral and peripheral air space consolidations and ground-glass opacities in the lower and upper lobes (a); two months after the onset of the disease, residual ground-glass opacities were still present in the right lower lobe (b).

Table 1
Evolution of laboratory tests in the patient with Crohn’s disease and COVID-19 pneumonia.

She presented a moderate COVID-19 pneumonia, and was admitted for clinical monitoring due to her immunosuppression. The patient only received supportive measures and there was no need of supplemental oxygen. Regarding the medical therapy of CD, azathioprine was withdrawn and adalimumab plus prednisone were maintained. The dose of adalimumab was administered on April 7, 2020 as scheduled. On the seventh day of hospitalization, she was discharged and given codeine for cough relief, which completely disappeared on April 13, 2020. On the same day, she repeated the SARS-CoV-2 RT-PCR on respiratory specimens and the result was negative. There was improvement of inflammatory markers as shown in Table 1. Two months later, a chest CT scan still showed residual ground-glass opacities in the lower lobes (Figure 1B). There was no CD exacerbation and the fecal calprotectin was normal (12 μg/g. Reference range: < 50 μg/g).

DISCUSSION

Patients treated with immunosuppressive drugs are at higher risk of developing more serious infections and atypical clinical presentations that may delay the diagnosis and/or lead to poorer outcomes. Immunosuppression has also been associated with severe illness and higher COVID-19 mortality55. Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19) [cited 2020 Nov 23]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Fneed-eXtraprecautions%2Fgroups-at-higher-risk.html
https://www.cdc.gov/coronavirus/2019-nco...
. However, this risk is probably not the same for all immune suppressive drugs. One of the exceptions could be the group of TNF inhibitors, such as adalimumab, which is a humanized monoclonal antibody that binds to TNF-α blocking the interaction with its soluble and membrane-bound receptors66. Scheinfeld N. Adalimumab: a review of side effects. Expert Opin Drug Saf. 2005;4:637-41..

Our patient had a moderate COVID-19, as she presented lower respiratory tract symptoms and lung abnormalities on the chest CT, compatible with pneumonia by SARS-CoV-2, without hipoxemia77. World Health Organization. Clinical management of COVID-19: interim guidance, 27 May 2020. Geneva: WHO; 2020. [cited 2020 Nov 23]. Available from: https://apps.who.int/iris/handle/10665/332196
https://apps.who.int/iris/handle/10665/3...
. She exhibited a favorable disease course even maintaining the adalimumab before and after the COVID-19 onset. The young age and female gender are possible explanations for this benign evolution, because both factors are related to better outcomes. The increasing age is associated with severe disease and higher mortality rates in COVID-19, especially in people aged 60 years or older88. Wu Z, McGoogan JM. Characteristics of and important lessons from the Coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020;323:1239-42.

9. Onder G, Rezza G, Brusaferro S. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy. JAMA. 2020;323:1775-6.
-1010. Williamson EJ, Walker AJ, Bhaskaran K, Bacon S, Bates C, Morton CE, et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature. 2020;584:430-6.. Women produce less inflammatory cytokines during the course of COVID-19, which is associated with a shorter disease duration and higher survival rates1111. Conti P, Younes A. Coronavirus COV-19/SARS-CoV-2 affects women less than men: clinical response to viral infection. J Biol Regul Homeost Agents. 2020;34:339-43.. On the other hand, complications of COVID-19 can also occur in otherwise healthy and young people.

The treatment of Crohn’s disease with adalimumab might have contributed to stop the progression to severe disease by interfering with the TNF-alpha-driven inflammatory process that occurs in COVID-19. Severe COVID-19 pneumonia seems to be related to hyperinflammation driven by SARS-COV-2 infection, resembling a cytokine storm syndrome that is a consequence of the release of several pro-inflammatory chemokines and cytokines, including TNF-α, secreted mainly by macrophages and monocytes1212. Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LF. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol. 2020;20:363-74.. This uncontrolled exacerbated systemic inflammation response contributes to multiple organs failure and the development of the acute respiratory distress syndrome, acute kidney injuries, circulatory collapse, heart failure and central nervous system involvement1313. Patel BV, Wilson MR, O’Dea KP, Takata M. TNF-induced death signaling triggers alveolar epithelial dysfunction in acute lung injury. J Immunol. 2013;190:4274-82..

Our patient presented with a progressive increase of serum ferritin, CRP and DHL levels throughout the hospitalization. After the peak of the last adalimumab dose, the serum levels of these laboratorial markers decreased. Proinflammatory cytokines, such as IL-1β, IL-6 and TNF-α, promote the elevation of serum ferritin and CRP1414. Connelly KG, Moss M, Parsons PE, Moore EE, Moore FA, Giclas PC, et al. Serum ferritin as a predictor of the acute respiratory distress syndrome. Am J Respir Crit Care Med. 1997;155:21-5.. The increase of ferritin synthesis is part of the hypoferremic response that occurs early in inflammation1414. Connelly KG, Moss M, Parsons PE, Moore EE, Moore FA, Giclas PC, et al. Serum ferritin as a predictor of the acute respiratory distress syndrome. Am J Respir Crit Care Med. 1997;155:21-5.. Elevated serum LDH and CRP levels are associated with progression to respiratory deterioration and ARDS in patients with COVID-191515. Poggiali E, Zaino D, Immovilli P, Rovero L, Losi G, Dacrema A, et al. Lactate dehydrogenase and C-reactive protein as predictors of respiratory failure in CoVID-19 patients. Clin Chim Acta. 2020;509:135-8.,1616. Zhou Y, Ding N, Yang G, Peng W, Tang F, Guo C, et al. Serum lactate dehydrogenase level may predict acute respiratory distress syndrome of patients with fever infected by SARS-CoV-2. Ann Transl Med. 2020;8:1118..

The medical literature has already shown some adalimumab users that presented with uncomplicated forms of COVID-191717. Valenti M, Facheris P, Pavia G, Gargiulo L, Borroni RG, Costanzo A, et al. Non-complicated evolution of COVID-19 infection in a patient with psoriasis and psoriatic arthritis during treatment with adalimumab. Dermatol Ther. 2020;33:e13708.

18. Tursi A, Angarano G, Monno L, Saracino A, Signorile F, Ricciardi A, et al. COVID-19 infection in Crohn’s disease under treatment with adalimumab. Gut. 2020;69:1364-5.
-1919. Okeke F, Mone A, Swaminath A. The course of SARS-COV2 infection was not severe in a Crohn’s patient who administered maintenance anti-TNF therapy overlapping the early pre-symptomatic period of infection. Antibodies (Basel). 2020;9:42.. Narcisi et al.1717. Valenti M, Facheris P, Pavia G, Gargiulo L, Borroni RG, Costanzo A, et al. Non-complicated evolution of COVID-19 infection in a patient with psoriasis and psoriatic arthritis during treatment with adalimumab. Dermatol Ther. 2020;33:e13708. have described a case of a 57-year-old male patient with a 9- year history of psoriasis and psoriatic arthritis treated with adalimumab every 2 weeks for almost two years before the onset of COVID-19 symptoms and the development of lung pneumonia with no need of oxygen support. Papa et al.1818. Tursi A, Angarano G, Monno L, Saracino A, Signorile F, Ricciardi A, et al. COVID-19 infection in Crohn’s disease under treatment with adalimumab. Gut. 2020;69:1364-5. have also described a 30-year-old male with ileal Crohn’s disease, under treatment with mesalazine and adalimumab every other week for 5 years due to a steroid dependency. This patient developed a moderate COVID-19 pneumonia, evolved favorably and was completely asymptomatic on the fifth day of hospitalization.

Swaminath et al.1919. Okeke F, Mone A, Swaminath A. The course of SARS-COV2 infection was not severe in a Crohn’s patient who administered maintenance anti-TNF therapy overlapping the early pre-symptomatic period of infection. Antibodies (Basel). 2020;9:42. reported a case of a 60-year-old female nurse with a past medical history of autoimmune disease, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and ileocolonic inflammatory Crohn’s disease in endoscopic remission. Both, the joint and bowel complaints, have been controlled for many years on weekly adalimumab and methotrexate. This patient presented with a severe COVID-19 pneumonia but required supplemental oxygen only for 2 days and was discharged after five days of hospitalization.

The previously reported cases involved people aged 50 years or older that could be related to a worse prognosis. However, none of them was using corticosteroids and we cannot rule out the potential role of corticosteroid in mitigating the lung damage caused by inflammation in the present case. In the RECOVERY trial, the use of glucocorticoids, specifically dexamethasone, resulted in a lower mortality among patients with COVID-19 under mechanical invasive ventilation or noninvasive supplemental oxygen therapy with respect to the usual care2020. The RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19: preliminary report. N Engl J Med. 2020:NEJMoa2021436.. Nevertheless, no benefit was observed for patients with no oxygen therapy requirement2020. The RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19: preliminary report. N Engl J Med. 2020:NEJMoa2021436.. In our case, besides the fact that the patient did not require supplemental oxygen therapy, she was already on a regular prednisone regimen at a dose of 20 mg once a day, a lower dose than the calculated anti-inflammatory dose of dexamethasone used in the trial.

The American Gastroenterology Association recommends that patients with Inflammatory Bowel Disease (IBD) who develop COVID-19 should discontinue the biological therapy during the viral infection and restart it after the complete resolution of symptoms2121. Rubin DT, Feuerstein JD, Wang AY, Cohen RD. AGA clinical practice update on management of inflammatory bowel disease during the COVID-19 pandemic: expert commentary. Gastroenterology. 2020;159:350-7.. However, based on what we observed in this case, it is plausible that the use of adalimumab has had a double protection role against COVID-19 severity and the recurrence of CD, not necessarily requiring the withdrawing of the TNF-α inhibitor. In spite of also reducing the production of inflammatory cytokines by macrophages suppression function, we decided to stop the azathioprine due to the concern of a potential interference on T- and B-lymphocytes function2222. Pandya M, Gohel D, Patel M V. Evaluation of immunosuppressive effects of azathioprine and cyclophosphamide in CD1 mice flow cytometer. PTB Rep. 2016;2:35-40.,2323. Winkelstein A. The effects of azathioprine and 6 MP on immunity. J Immunopharmacol. 1979;1:429-54.. Thus, azathioprine could inhibit the cell-mediated immunity and the T-lymphocyte-dependent antibody synthesis against SARS-CoV-2.

The use of adalimumab may have influenced the oligosymptomatic presentation observed in our patient. This may have made the clinical suspicion of COVID-19 difficult and delayed the diagnosis. Fever and dyspnea, both absent in our patient, are common in COVID-19 pneumonia and upregulated TNF-α production is associated with flu-like symptoms, such as fever, malaise and lung injury1313. Patel BV, Wilson MR, O’Dea KP, Takata M. TNF-induced death signaling triggers alveolar epithelial dysfunction in acute lung injury. J Immunol. 2013;190:4274-82.,2424. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497-506.

25. Goyal P, Choi JJ, Pinheiro LC, Schenck EJ, Chen R, Jabri A, et al. Clinical characteristics of Covid-19 in New York City. N Engl J Med. 2020;382:2372-4.
-2626. Netea MG, Kullberg BJ, Van der Meer JW. Circulating cytokines as mediators of fever. Clin Infect Dis. 2000;31 Suppl 5:S178-84.. The patient had no digestive symptoms, which, if present, could be attributed to the COVID-19 itself and/or to a CD flare triggered by the infection. However, the levels of fecal calprotectin were normal, ensuring that CD remained in remission2727. Effenberger M, Grabherr F, Mayr L, Schwaerzler J, Nairz M, Seifert M, et al. Faecal calprotectin indicates intestinal inflammation in COVID-19. Gut. 2020;69:1543-4..

Moreover, the patient had a longer duration of symptoms than that seen in mild COVID-19 that is around two weeks2828. World Health Organization. WHO Director-General’s opening remarks at the media briefing on COVID-19: 24 February 2020. [cited 2020 Nov 23]. Available from: https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---24-february-2020
https://www.who.int/director-general/spe...
. It remains unclear whether this longer duration of symptoms is acompanied by a prolonged transmission period. Despite this, she underwent a new SARS-COV-2 RT-PCR on respiratory specimens and the negative result opposes this possibility. Unfortunately, it was not possible to repeat the COVID-19 test on other days.

CONCLUSION

We reported on a case of a young woman with severe Crohn’s disease that presented with COVID-19 pneumonia with a favorable outcome, without hypoxemia, despite maintaining the use of adalimumab and prednisone. This raises the hypothesis that it might not be mandatory to withdraw the TNF-α inhibitor adalimumab in patients with Crohn’s Disease presenting with COVID-19, especially in severe cases of CD. This drug could have a double protection role: stopping the progression to COVID-19 complications by blocking the TNF-α -driven inflammatory process that occurs in severe COVID-19 and maintaining CD remission. On the other hand, it is possible that the use of adalimumab makes the olygosymptomatic clinical presentation last longer than usual, contributing to the diagnosis delay.

REFERENCES

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    Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol. 2020;20:355-62.
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    Crespi M, Dulbecco P, De Ceglie A, Conio M. Strictures in Crohn’s disease: from pathophysiology to treatment. Dig Dis Sci. 2020;65:1904-16.
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    Schett G, Sticherling M, Neurath MF. COVID-19: risk for cytokine targeting in chronic inflammatory diseases? Nat Rev Immunol. 2020;20:271-2.
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  • 9
    Onder G, Rezza G, Brusaferro S. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy. JAMA. 2020;323:1775-6.
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    Williamson EJ, Walker AJ, Bhaskaran K, Bacon S, Bates C, Morton CE, et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature. 2020;584:430-6.
  • 11
    Conti P, Younes A. Coronavirus COV-19/SARS-CoV-2 affects women less than men: clinical response to viral infection. J Biol Regul Homeost Agents. 2020;34:339-43.
  • 12
    Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LF. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol. 2020;20:363-74.
  • 13
    Patel BV, Wilson MR, O’Dea KP, Takata M. TNF-induced death signaling triggers alveolar epithelial dysfunction in acute lung injury. J Immunol. 2013;190:4274-82.
  • 14
    Connelly KG, Moss M, Parsons PE, Moore EE, Moore FA, Giclas PC, et al. Serum ferritin as a predictor of the acute respiratory distress syndrome. Am J Respir Crit Care Med. 1997;155:21-5.
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    Poggiali E, Zaino D, Immovilli P, Rovero L, Losi G, Dacrema A, et al. Lactate dehydrogenase and C-reactive protein as predictors of respiratory failure in CoVID-19 patients. Clin Chim Acta. 2020;509:135-8.
  • 16
    Zhou Y, Ding N, Yang G, Peng W, Tang F, Guo C, et al. Serum lactate dehydrogenase level may predict acute respiratory distress syndrome of patients with fever infected by SARS-CoV-2. Ann Transl Med. 2020;8:1118.
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    Valenti M, Facheris P, Pavia G, Gargiulo L, Borroni RG, Costanzo A, et al. Non-complicated evolution of COVID-19 infection in a patient with psoriasis and psoriatic arthritis during treatment with adalimumab. Dermatol Ther. 2020;33:e13708.
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    Tursi A, Angarano G, Monno L, Saracino A, Signorile F, Ricciardi A, et al. COVID-19 infection in Crohn’s disease under treatment with adalimumab. Gut. 2020;69:1364-5.
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    Okeke F, Mone A, Swaminath A. The course of SARS-COV2 infection was not severe in a Crohn’s patient who administered maintenance anti-TNF therapy overlapping the early pre-symptomatic period of infection. Antibodies (Basel). 2020;9:42.
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    The RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19: preliminary report. N Engl J Med. 2020:NEJMoa2021436.
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    Rubin DT, Feuerstein JD, Wang AY, Cohen RD. AGA clinical practice update on management of inflammatory bowel disease during the COVID-19 pandemic: expert commentary. Gastroenterology. 2020;159:350-7.
  • 22
    Pandya M, Gohel D, Patel M V. Evaluation of immunosuppressive effects of azathioprine and cyclophosphamide in CD1 mice flow cytometer. PTB Rep. 2016;2:35-40.
  • 23
    Winkelstein A. The effects of azathioprine and 6 MP on immunity. J Immunopharmacol. 1979;1:429-54.
  • 24
    Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497-506.
  • 25
    Goyal P, Choi JJ, Pinheiro LC, Schenck EJ, Chen R, Jabri A, et al. Clinical characteristics of Covid-19 in New York City. N Engl J Med. 2020;382:2372-4.
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    Netea MG, Kullberg BJ, Van der Meer JW. Circulating cytokines as mediators of fever. Clin Infect Dis. 2000;31 Suppl 5:S178-84.
  • 27
    Effenberger M, Grabherr F, Mayr L, Schwaerzler J, Nairz M, Seifert M, et al. Faecal calprotectin indicates intestinal inflammation in COVID-19. Gut. 2020;69:1543-4.
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    World Health Organization. WHO Director-General’s opening remarks at the media briefing on COVID-19: 24 February 2020. [cited 2020 Nov 23]. Available from: https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---24-february-2020
    » https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---24-february-2020

  • ETHICAL APPROVAL. The patient has given permission and has signed the informed consent for the publication of this case report.

  • FUNDING.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Publication Dates

  • Publication in this collection
    18 Dec 2020
  • Date of issue
    2020

History

  • Received
    22 Oct 2020
  • Accepted
    23 Nov 2020
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